Tag: foetal development

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Antiseizure Drugs during Pregnancy may Affect Neurodevelopment

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Children whose mothers have taken antiseizure drugs during pregnancy are more likely than others to receive a neuropsychiatric diagnosis. This is according to a comprehensive study by researchers at Karolinska Institutet and elsewhere, published in Nature Communications. However, the researchers emphasise that the absolute risk is low.

Antiseizure drugs are used to treat epilepsy and to stabilise mood in certain psychiatric conditions. However, some of these drugs, such as valproate, are known to affect the foetus if used during pregnancy. 

The current study included data from over three million children in the UK and Sweden, 17 495 of whom had been exposed to antiseizure drugs during pregnancy. 

As expected, children exposed to valproate were more likely to be diagnosed with autism, intellectual disability or ADHD compared to children not exposed to antiseizure drugs. Children exposed to topiramate had a 2.5-fold increased risk of intellectual disability, while those exposed to carbamazepine had a 25 per cent increased risk of being diagnosed with autism and a 30 per cent increased risk of intellectual disability. 

No increased risk with lamotrigine 

However, the researchers found no evidence that taking the antiseizure drug lamotrigine during pregnancy increases the risk of neuropsychiatric diagnoses in the child. 

“Our findings suggest that while certain medications may pose some risk, lamotrigine may be a less risky option, but active monitoring of any antiseizure medication is critical to ensure safety and effectiveness, particularly during pregnancy,” says Brian K. Lee, Professor at Drexel University Dornsife School of Public Health, USA, and affiliated researcher at the Department of Global Public Health, Karolinska Institutet, Sweden. 

The researchers emphasise that the absolute risk of the child receiving a neuropsychiatric diagnosis is low and that there may also be risks associated with not taking antiseizure medication during pregnancy. 

“If you’re pregnant or trying to become pregnant, and taking one of these medications, it may be worth talking with your physician to make sure you’re taking the best medicine for your needs, while minimising risk to future children,” says Viktor H. Ahlqvist, researcher at the Institute of Environmental Medicine, Karolinska Institutet, and joint first author with Paul Madley-Dowd at the University of Bristol, UK. 

The results support previous findings from smaller studies that found links between antiseizure drugs during pregnancy and the risk of neuropsychiatric diagnoses in the child. One difference is that the new study found no statistically significant association between topiramate or levetiracetam and ADHD in the child. 

Source: Karolinska Institutet

Categories : Genetics Obstetrics & GynaecologyTags :

A Tiny Chromosomal Deletion is Linked to Spina Bifida

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A group of researchers at the University of California San Diego School of Medicine led an investigation that offers new insight into the causes of spina bifida, the most common structural disorder of the human nervous system.

The group’s work reveals the first link between spina bifida and a common chromosomal microdeletion in humans. The study demonstrates that individuals carrying this chromosomal deletion – present in one of 2500 live births – demonstrate a risk of spina bifida more than 10 times greater than the general public.

The study, published in Science, also underscores the potential role of folic acid (aka vitamin B-9) in reducing the risk of spina bifida.

Professor Joseph G. Gleeson at Rady Children’s Institute for Genomic Medicine, is the senior author of the study. He explained that spina bifida, also known as meningomyelocele, affects one in every 3000 newborns. Unfortunately, the causes are mostly unknown. A few mutations were reported but could only explain a tiny fraction of risk, Gleeson added.

To uncover the genetic causes of the disease, Gleeson’s UC lab joined with colleagues around the world to establish the Spina Bifida Sequencing Consortium in 2015. The consortium began focusing on a tiny deletion in chromosome 22. Chromosome microdeletions refer to a condition in which several genes in a chromosome are missing. The group’s target condition, known as 22q11.2del, has been implicated in a number of other disorders. They began looking for 22q11.2del in spinal bifida patients.

“All patients we recruited have the most severe form of spina bifida, and all underwent best-practice comprehensive genomic sequencing,” Gleeson said. “We identified 22q11.2del in 6 out of 715 patients. This may not seem a high percentage, but this is by far the most common single genetic variation that could contribute to spina bifida.”

He went on to say the group identified eight additional spina bifida patients who carried the deletion from a cohort of approximately 1500 individuals recruited because of the presence of the common 22q11.2 deletion, Gleeson said.

The researchers then narrowed the cause among the many genes in the 22q11.2 deletion to a single gene known as CRKL. Gleeson explained that there are nine other genes in this chromosomal region that could have been the cause. He said the team began a process of elimination, “knocking out” each of the mouse genes one-by-one, when they received a fortuitous email from Dolores Lamb from Weil Cornell College of Medicine. Lamb had noted some of the mice in their vivarium that were missing Crkl and showed spina bifida. (Study co-first author Keng Ioi Vong, PhD, explained that researchers use all capital letters to describe the gene in humans, and lower-case for mice.) Lamb’s group heard about the Gleeson lab project through the Spina Bifida Association.

“This finding really got us excited because it meant that CRKL disruption might be sufficient for spina bifida,” said Vong. “We removed the mouse Crkl gene ourselves and confirmed that some of the mice developed neural tube defects, including spina bifida.” Most of the other genes in 22q11.2 deletion were subsequently excluded, he added.

They next turned their attention to how folic acid may modulate CRKL-mediated spina bifida. Vong noted that prior studies in humans demonstrated that folic acid supplementation prior to conception reduces the incidence of spina bifida and other neural tube defects by up to 30-50 %, but the mechanisms are still a mystery.

“When we deprived the Crkl mutant female mice of folic acid in their chow, many more of their offspring had neural tube defects, and the severity increased dramatically,” Vong explained. “This suggests that folic acid taken by pregnant women may not only reduce the risk, but also the severity of neural tube defects in their offspring.”

“We hope our findings can help the research community to better understand causes of neural tube defects, especially the causes attributable to common genetic findings like 22q11.2 deletion,” Gleeson said. “We also hope our findings can contribute to healthy pregnancies, improved women’s health, and improved outcomes for children.”

Source: University of California – San Diego

Categories : Ethics and Law NeurologyTags :

Are Brain Organoids Derived from Foetal Tissue Ethical?

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Brain organoids (BOs), though often referred to as “mini brains,” are not truly human brains. But the concerns over these lab-grown brain tissues, especially when they are developed from human foetal tissues, can be very human indeed.

In a paper published in EMBO Reports, researchers from Hiroshima University offer valuable insights into the complexities inherent in brain organoid research, highlighting often-overlooked ethical dilemmas for better decision-making, especially for foetal brain organoids (FeBOs).

Brain organoids are three-dimensional human brain tissues derived from stem cells. They replicate the complexity of the human brain in vitro, allowing researchers to study brain development and diseases.

Traditionally, brain organoids (BOs) are grown from pluripotent stem cells, an especially potent sub-type that is typical of early embryonic development, but new technologies now make it possible to generate these organoids from human foetal brain cells.

The research comes amid increasingly heated debates over human BOs. Central concerns are that lab-grown BOs might achieve consciousness and the ethical implications of transplanting them into animal models. The discourse includes matters of consent, commercialisation, integration with computational technologies, and legal ramifications. In addition, the public perception of BOs, often shaped by inaccurate media depictions.

Issues of consciousness arising and transplantation into animal models are particularly morally sensitive for tissue donors, and so rigorous informed consent is needed. With FeBOs, these become even more important. FeBOs, for example, can grow past the developmental stage of the initial foetal donor tissue.

“Our research seeks to illuminate previously often-overlooked ethical dilemmas and legal complexities that arise at the intersection of advanced organoid research and the use of foetal tissue, which is predominantly obtained through elective abortions,” said Tsutomu Sawai, an associate professor at Hiroshima University and lead author of the study.

The study highlights the urgent need for a sophisticated and globally harmonised regulatory framework tailored to navigate the complex ethical and legal landscape of FeBO research. One example is the 14-day rule used in embryo research, as neurogenesis does not occur in embryos prior to 14 days post-fertilisation. Using FeBOs derived from 12-15 week old foetuses therefore raises significant ethical questions, especially as there is a proposed 20-week ethical boundary.

The paper emphasises the importance of informed consent protocols, ethical considerations surrounding organoid consciousness, transplantation of organoids into animals, integration with computational systems, and broader debates related to embryo research and the ethics of abortion.

“Our plan is to vigorously advocate for the development of thorough ethical and regulatory frameworks for brain organoid research, including FeBO research, at both national and international levels,” said Masanori Kataoka, a fellow researcher at Hiroshima University.

“Rather than being limited to issues of consciousness, it’s imperative, now more than ever, to systematically advance the ethical and regulatory discussion in order to responsibly and ethically advance scientific and medical progress,” Sawai said.

Moving forward, the research duo plans to continue supporting the advancement of ethical and regulatory discussions surrounding brain organoid research. By promoting responsible and ethical progress in science and medicine, they aim to ensure that all research involving brain organoids, including FeBOs, is conducted within a framework that prioritises human dignity and ethical integrity.

Source: Hiroshima University

Categories : Obstetrics & GynaecologyTags :

Foetal Exposure to THC could Lead to Long-lasting Health Impacts

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Consuming THC (Delta-9-tetrahydrocannabinol) while pregnant could potentially affect development of the foetus and lead to life-long health impacts for offspring, according to a new study published in the journal Clinical Epigenetics.

THC is the main psychoactive ingredient in cannabis, which is growing in popularity and availability. The prevalence of cannabis use in pregnancy is also rapidly increasing, especially during the first trimester, when the foetus is most vulnerable to environmental exposures, to mitigate common symptoms like morning sickness. However, the potential effects of prenatal cannabis use on foetal development remain inconclusive, in part due to a lack of safety data. This study aimed to identify the potential long-term health impacts of THC use during pregnancy.

In a non-human primate model, Oregon Health & Science University researchers found that exposing a pregnant subject to THC altered placental and foetal epigenetics. Researchers also found that that these changes to gene regulation and expression are consistent with those seen with many common neurobehavioural conditions, including autism spectrum disorder.

“Cannabis is one of the most commonly used drugs and is widely available across the country, so there is a common perception that its completely safe to use,” said the study’s lead author Lyndsey Shorey-Kendrick, PhD, a computational biologist in the Division of Neurosciences at OHSU’s Oregon National Primate Research Center, or ONPRC. “The reality is that cannabis still carries many health risks for certain populations, including those who are pregnant. If we’re able to better understand the impacts, we can more effectively communicate the risks to patients and support safer habits during the vulnerable prenatal period.”

In a model using nonhuman primates, researchers administered THC in a daily edible and compared its effects to a group receiving a placebo. Specifically, researchers evaluated the epigenetic changes in several key areas that indicate healthy prenatal development: the placenta and foetal lung, brain and heart.

When looking at these areas, analyses showed that THC exposure altered the epigenome, meaning a process in which the information encoded in a gene is turned into a function or observable trait. Genes are all specifically coded to contribute to different functions of the body and brain, so any impact on epigenetic processes due to drug exposure is concerning, especially during a critical developmental window such as pregnancy.

Researchers found that significant changes involved genes associated with common neurobehavioral disorders, including autism spectrum disorder and attention deficit hyperactivity disorder. These conditions are linked to adverse health outcomes in childhood and adolescence, including poorer memory and verbal reasoning skills, and increased hyperactivity, impulsivity and inattention.

The research team hopes findings from this study will add to the limited existing literature on THC use during pregnancy, and help guide patient counselling and public health polices focused on cannabis in the future.

“It’s not common practice for providers to discuss cannabis use with patients who are pregnant or trying to conceive,” said the study’s corresponding author, Jamie Lo, MD, MCR, associate professor of obstetrics and gynaecology (maternal-foetal medicine) at OHSU. “I hope our work can help open up a broader dialogue about the risks of cannabis use in the preconception and prenatal period, so we can improve children’s health in the long run.”

Source: Oregon Health & Science University

Categories : Neurology Obstetrics & GynaecologyTags :

Low Maternal Vitamin D Levels may Increase Schizophrenia Risk of Offspring

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Neuroscientists published in the Journal of Neurochemistry, shows that maternal levels of vitamin D are key in the development of dopaminergic neurons, which are thought to be involved in schizophrenia.

Professor Darryl Eyles has built on past research out of his laboratory at the Queensland Brain Institute linking maternal vitamin D deficiency and brain development disorders, such as schizophrenia, to understand the functional changes taking place in the brain.

Schizophrenia is associated with many developmental risk factors, both genetic and environmental. While the precise neurological causes of the disorder are unknown, what is known is that schizophrenia is associated with a pronounced change in the way the brain uses dopamine, the neurotransmitter often referred to as the brain’s ‘reward molecule’.

Professor Eyles has followed the mechanisms that might relate to abnormal dopamine release and discovered that maternal vitamin D deficiency affects the early development and later differentiation of dopaminergic neurons.

The team at the Queensland Brain Institute developed dopamine-like cells to replicate the process of differentiation into early dopaminergic neurons that usually takes place during embryonic development.

They cultured the neurons both in the presence and absence of the active vitamin D hormone. In three different model systems they showed dopamine neurite outgrowth was markedly increased. They then showed alterations in the distribution of presynaptic proteins responsible for dopamine release within these neurites.

“What we found was the altered differentiation process in the presence of vitamin D not only makes the cells grow differently, but recruits machinery to release dopamine differently,” Professor Eyles said.

Using a new visualisation tool known as false fluorescent neurotransmitters, the team could then analyse the functional changes in presynaptic dopamine uptake and release in the presence and absence of vitamin D.

They showed that dopamine release was enhanced in cells grown in the presence of the hormone compared to a control.

“This is conclusive evidence that vitamin D affects the structural differentiation of dopaminergic neurons.”

Leveraging advances in targeting and visualising single molecules within presynaptic nerve terminals has enabled Professor Eyles and his team to further explore their long-standing belief that maternal vitamin D deficiency changes how early dopaminergic circuits are formed.

The team is now exploring whether other environmental risk factors for schizophrenia such as maternal hypoxia or infection similarly alter the trajectory of dopamine neuron differentiation.

Eyles and his team believe such early alterations to dopamine neuron differentiation and function may be the neurodevelopmental origin of dopamine dysfunction later in adults who develop schizophrenia.

Source: University of Queensland

Categories : Ethics and Law Obstetrics & GynaecologyTags :

High Court Wrong about Law on Foetuses under 26 Weeks, Concourt Rules

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The Constitutional Court has declined to confirm the constitutional invalidity of sections of the Births and Deaths Registration Act. This comes after the Pretoria High Court found that the Act denied parents the right to bury the remains of a foetus less than 26-weeks.

The application was brought by The Voice of the Unborn Baby NPC and the Catholic Archdiocese of Durban against the ministers of Home Affairs and Health.

The applicants argued that the Act was “insensitive, hurtful and disrespectful” as it only allows for a death certificate to be issued in “stillborn” cases when the foetus is more than 26-weeks.

High Court Judge Nomonde Mngqibisa-Thusi agreed and ruled that sections of the Act are unconstitutional on the basis it “deemed a foetus less than 26-weeks to be medical waste that must be incinerated”.

However, the Constitutional Court, in a unanimous judgment, said the judge was wrong. Acting Judge Pula Tlaletsi said the applicants had submitted that the provisions of the Act had the effect that no burial order could be issued for foetuses lost through miscarriage before the 26-week mark, and that the regulations only made provision for the burial of corpses and human remains, but not foetal remains.

“While it may be true, as the applicants argued, that throughout the years the practice has been to deny parents this right in the apparent belief that this is what the law provides, matters not. The Act contains no such prohibition,” Judge Tlaletsi said.

“The relevant sections cannot be declared inconsistent with the Constitution because of such omission … the Act does not stand in the way of that burial,” he said, noting that the Act only regulated the burial of “dead human bodies or still-born children”.

The Judge said that the court was not in a position to grant the relief.

Read the judgment here

The question as to what medical staff at public hospitals must do if parents expressed the wish to bury or cremate pre-viable foetal remains was not clear, he said.

“Such a burial or cremation would no doubt require the cooperation of healthcare professionals and public hospitals would be expected to allocate the necessary resources.

“Because of the way the case was pleaded, we do not have the necessary evidence to evaluate considerations relating to how hospitals would manage this … There may be other restrictions, for example, limitations imposed by municipal regulations (regarding cemeteries and crematoriums).”

The Catholic Church, arguing that its members held “sincere religious beliefs” that they become parents from the moment of conception, said the burial right should also extend to lost pregnancies “due to human intervention”, including termination of pregnancies.

But two amici in the case — the Women’s Legal Centre Trust and the Sexual and Reproductive Justice Coalition — said this would have a profound impact on the termination of pregnancy services offered to women, and the attached confidentiality.

This burden, they said, would lead to a decrease in facilities offering termination and a diminution of sexual and reproductive rights.

However, the apex court did not comment on this.

By Tania Broughton

Republished from GroundUp under a Creative Commons Attribution-NoDerivatives 4.0 International License.

Source: GroundUp

Categories : NeurologyTags :

Foetal Brain Development Mapped in Great Detail

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Researchers at Karolinska Institute have charted a highly detailed molecular atlas of the foetal development of the brain.

The study, published in Nature, made use of single-cell technology which was performed on mice. In this way, researchers have identified almost 800 different cells that are active during foetal development – far more than previously known.

“Brain development is well described and the main cell types are known. What is new about our atlas is the high resolution and detail,” said Sten Linnarsson, head of research and professor at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet.

In their work, the researchers followed the brain development of the mice from day seven, when the brain is just forming, to the end of pregnancy on day 18.

Using single-cell technology, they were able to identify the detailed composition of the brain during foetal development: what cell types exist, how many cells of each type, and how this changes at the various stages of development.

The researchers also studied gene activity in each individual cell, classifying cells according to these activity patterns.

Creating a molecular atlas

The result is a molecular atlas that accurately illustrates how all cells in the brain develop from the early embryo. The atlas shows, for example, the way early neural stem cells first increase and then decrease in number, being replaced by transitional forms in several waves that eventually mature into ready-made neurons.

The researchers also demonstrated how early stem cell lines branch much like a family tree, giving rise to several different types of mature cells. The next step is mapping out atlases of the human brain, both in adults and during foetal development.

“Atlases like this are of great importance for research into the brain, both to understand brain function and its diseases. Cells are the body’s basic building blocks and the body’s diseases are always expressed in specific cells. Genes that cause serious diseases are found in all of the body’s cells, but they cause disease only in specific cells in the brain,” said Prof Linnarsson.

Source: Karolinska Institute

Journal information: “Molecular Architecture of the Developing Mouse Brain”, Gioele La Manno, et al. Nature, online 28 July 2021, doi:10.1038/s41586-021-03775-x.